The intake of calorie-rich fast food and sedentary lifestyles of developed countries has sharply increased the incidence of obesity. The obesity pandemic is thought to be associated with a sedentary lifestyle and the overconsumption of energy-rich food. Obesity is not only a serious health and economic burden, but also predisposes a person to a variety of metabolic diseases (i.e., the coexistence of several risk factors for atherosclerosis, hyperglycemia, dyslipidemia, and hypertension). Obesity occurs when adipose cells increase excessively in size (hypertrophy) and/or number (hyperplasia). Animal studies suggest that hyperplasia occurs in 2 steps: an increase in numbers of preadipocytes and differentiation of preadipocytes into mature (adipokine-secreting) adipocytes.
Anti-obesity strategies are classified into four categories: reducing food intake, blocking nutrient absorption, increasing thermogenesis, and modulating fat or protein metabolism or storage. There are currently two drugs approved by the FDA for the treatment of obesity. These include orlistat that blocks the absorption of dietary fat, and sibutramine, a specific re-uptake inhibitor for norepinephrine and serotonin that acts in the central nervous system (CNS) to reduce energy intake. These drugs have limited efficacies and side effects are commonly reported, which are further confounded by diminishing response in the long-term treatment of obesity. Moreover, anti-obesity drug development strategy continues to focus on either central or peripheral acting inhibitors of food intake, which will likely encounter similar problems.
Adipocyte differentiation has often been a target of anti-obesity strategies, because obesity is caused not only by hypertrophy of adipocytes, but also by adipocyte hyperplasia. Blocking of adipocytes differentiation is one of the anti-obesity strategies falling under the category of modulating fat storage.
Furthermore, modulation of the state of differentiation and growth of cancer cells, i.e. differentiation therapy may be beneficial to cancer treatments.
The current drugs used in cancer treatment are highly toxic and often non-specific. Current anticancer therapy strategies are more focused on rapid proliferating cells, which can shrink primary and metastatic tumors, but such effects are usually transient and tumor relapse of most metastatic cancers frequently occur. One possible reason for failure is the existence of cancer stem cells. Unlike most cells within the tumor, cancer stem cells are resistant to well-defined chemotherapy, and after treatment, they can regenerate all the cell types in the tumor through their stem cell-like behavior of largely quiescent nature and their abundant expression of drug transporters.
Therefore, there exists a need to find new compounds that can modulate cell cycle of adipocyte and/or cancer cells to provide treatment or prevention of obesity and/or cancers.